Pharmacokinetics 3 & 4 (Kyle) Flashcards
What mediates elimination of a drug from the system?
Metabolism and excretion
What are the two aspects of accumulation of a drug?
Absorption and distribution
What determines the onset of a drug and its peak intensity?
The accumulation of a drug in the body as well as movement to its site of action.
What is biotransformation?
The chemical modification of xenobiotics by endogenous enzymes
What is metabolism?
Often used to refer to the chemical transformation of anabolic and catabolic reactions (protein fat carbs nucleic acids hormones and neurotransmitters) but is often used to refer to the chemical transformation of both endogenous and exogenous agents.
What is the formula for Michaelis- Menton kinetics?
V= Vmax [S] / (Km + [S] )
In MM kinetics the rxn rate is proportional to what?
To the lecel of enzyme at saturating substrate concentrations.
What is a phase 1 reaction?
Converts the parent drug to an inactive metabolite by introducing an unmasking metabolite.
What is a disadvantageous aspect of phase 1 reactions?
The generation of free radicals.
Describe phase 2 reactions?
Phase two reactions lead to the addititon of a functional group onto the parent compound or reactive product of a phase 1 reaction.
Where does biotransformation primarily take place?
In the liver
What subcellular space are the majority of metabolizing enzymes found?
The endoplasmic reticulum and the cytosol. There is also additional activity found in the nuclear envelope and the plasma membrane.
What does the ER fragment into?
Microsomes.
Where do most of the phase 1 reactions take place?
Endoplasmic reticulum
Where are the wnzymes responsible for the phase 2 reactions locaized?
Cytosolic fragment
What is the first step of a phase 1 reaction?
Oxidation which is the addition of oxygen or the removal of hydrogen
What is the second step of a phase 1 reaction?
Reduction which remember adds a hydrogen or removes an oxygen
What is the third step of a phase 1 reaction?
Hydrolysis- remember this is the addition of water with the breakdown of molecule. performed in blood plasma and liver by esterases.
This is the breakdown of an ester to an alcohol and acid.
What is gluronidation
This is the most extensive conjugation reaction present in the body. aliphatic alcohols and phenols are commonly conjugated with glucronide.
What is acylation?
Acylation especially acetylation with an acetyl group for example sulfonamides.
What does glutathione (GSH)
A conjugation of the tripeptide of glutamate- cysteine-glycine which lead to a mercapturic acid metabolite.
What is the general trend of the products of phase 2 reactions.
The resultant metabolite is more water soluble and less lipid soluble. thus less drug is reabsorged from the kidney . Note acetylated metabolites are often less water soluble.
What is cytochrome p450
Primarily a catalyst for phase 1 biotransformation.
Where is the conc of cyp450 ?
In the liver
Why are Cyp450’s called mixed function system?
because the enxymes have a broad and overlapping substrate specificity. ( nonspecific)
What cyp450’s are involved in the majority of bio-transformations?
CYP 1-3
What is CYP34A mainly responsible for?
It is responsible for the metabolism of drugs that are absorbed in the GI tract.
***It decreases bioavailability
What makes up the CYP450 enzyme complex?
The CYP 450 enzyme and CYP 450 reductase
What are the major factors that affect drug metabolism?
A. Species differences B. Genetic Differences, polymorphisms C. Age Differences D. Sex E. Diet F. Disease
What is induction?
What is the opposite of induction?
Drug induced changes in metabolism, over time many drugs can cause an increase over time in liver enzymes
Inhibition
Is induction a reversible process?
YES
Describe the time characteristics of induction?
- Onset is 3-12 hours
- Maximal 1-5 days
- Persistance 5-12 days.
Describe the inhibitory action of drug induced metabolism changes.
Drug metabolism can be subject to competitive inhibition.
What are some mechanisms of drug induced inhibition?
- Competition among substrates
- Inactivation by formation of a tight complex with heme
- Depletion of cofactors
- Enzyme inhibitors
- Increase degradation
Pharmacogenetics, what is this?
the genetic basis for differences among the population in drug responses. ( therapeutic or toxic)
What is pharmacogenomics?
The application of genomic information towards the discovery and development of novel specific drugs. Such drugs may be targeted for selective use among specific patient populations.
What are the common mechanisms by which genetics variations can control metabolism include?
- Competition by loss of activity
- reduced catalytic activity
- enhanced catalytic activity
What is drug excretion?
Excretion is the removal of drug from the body and is a component of drug elimination which represents the combined action of metabolism and excretion. Drugs can be excreted as a parent compound or as a metabolite.
What are the six routes of drug excretion?
- Renal - in the urine
- Liver / intestines- in the feces
- Lungs- the major routes for inhaled agents
- sweat- minor
- saliva- minor
- breast milk
What is the major organ for drug excretion?
The kidney
What is the functional unit of the kidney?
Nephron
What are the three major processes that go on in the kidney that are responsible for drug excretion?
- Glomerular filtration- bowmans capsule
- Tubular secretion
- Tubular reabsorption
How much of the blood that enters the glomeruli is filtered? What is this filtered component called?
20% which ends up being 110-130 ml/min
Glomerular filtration rate
How is GFR calculated?
By the clearance of creatinine
In bowmans capsule what types of molecules are filtered out of the blood?
Molecules of low molecular weight (ions, glucose and peptides but ot proteins.
What will inhibit a drug from elimination in the glomeruleris?
If it is tightly bound to a plasma protein.
Where in the kidney is water reabsorbed?
Where are weak electrolytes secreted?
In the proximal tubule, there is reabsorption of water and the active secretion of weak electrolytes.
Is Glomular filtration an active or passive process?
It is passive and non saturable
Is the secretion of electrolytes an active or passive process?
Secretion of electrolytes is an active process requiring a transport protein an a supply of energy
How do you quantify the renal excretion of drugs?
The renal clearance value
If a drug is filtered but not secreted or reabsorbed what will renal clearance be?
120 ml/min in normal subjects
Clr = GFR
If the renal clearance is less than 120 ml / min then the drug will show __________ ?
Net reabsorption ( CLr < GFR )
If the renal clearance is greater than 123 ml / min then how does GFR relate to CLr ?
When renal clearance is greater than 120 ml / min then tubular secretion must be contributing to the elimination process
(CLr > GFR )
Describe the transport mechanisms present in the liver.
Transport mechanisms in the liver are similiar to the proximal tubule of the kidney are also present in the liver. These processes actively secrete drugs and metabolites
